An invariant feature of HIV and SIV pathogenesis is CD4 tropism, mediated by a highly conserved CD4 binding site on the envelope glycoprotein. By focusing infection onto T-cell subsets that provide help for adaptive immunity (e.g. Th1, Th17, Tfh), it is likely that CD4 tropism has profound effects on antiviral immune responses, which are ultimately inadequate to contain viral replication and disease progression. Binding of gp120 to CD4 also has the potential to disrupt CD4's physiologic interaction with HLA class-II on antigen presenting cells, which underlies T-cell immunologic helper functions. We are exploring a highly innovative hypothesis that lentiviruses engineered to retain infectivity while lacking a CD4 binding site and CD4 tropism would be fundamentally altered in their pathogenesis, enabling more potent helper T-cell functions to be generated that are typically not permitted in the context of CD4-tropic infection. An understanding of the possible expansion in the repertoire of antiviral immune responses in this context could be informative for the HIV vaccine field. We have derived a highly CD4-independent variant of SIVmac239 and shown that it is infectious in vitro and in vivo in rhesus macaques even after its CD4 binding site has been ablated. This virus, termed iMac-?D, replicates to a high acute peak in plasma and is then controlled to elite levels; infects macrophages and other non-T-cell types; does not deplete CD4+ T-cells; spares cortical T-cell regions in nodes; and generates high and sustained levels of neutralizing antibodies long after plasma viremia is cleared. This first non-CD4 tropic primate lentivirus will be evaluated with 4 specific aims: 1) To define and characterize in vivo its pathogenicity, tropism, and qualitative and/or quantitative differences in host humoral and cellular antiviral immune responses compared to CD4-tropic SIVmac239 infection; 2) To identify components of the host adaptive immune response responsible for iMac-?D's control and to determine if they can protect animals from a pathogenic heterologous SIV challenge; 3) To further examine the effects of CD4 interactions by evaluating pathogenicity and immunological parameters of infection when this virus retains its CD4 binding site; and 4) To extend this approach to an HIV-1 envelope glycoprotein by creating and characterizing in vitro and in vivo a non-CD4 tropic, simian/human immunodeficiency virus (SHIV) that, like iMac- D, can replicate in rhesus PBMCs and macaques while lacking a CD4 binding site. This non-CD4 tropic SHIV will provide a bridge to further studies that will be relevant to anti-HIV-1 immune responses in the setting of CD4+ helper T-cell sparing. These unique viruses and this novel model will enable us to address new and potentially paradigm-shifting themes of HIV and SIV pathogenesis and vaccine design.